Processes for preparation of 4-aminoindane derivatives and related aminoindane amides

ABSTRACT

A process for preparation of 4-aminoindane derivatives of a first formula, salts and enantiomers thereof comprising the steps of: a) hydrogenating a 1,2-dihydroquinoline of a second formula to give a corresponding tetrahydroquinoline of a third formula; b) acylating the tetrahydroquinoline of the third formula with a carboxylic acid derivative of a fourth formula to obtain a corresponding acyl derivative compound of a fifth formula; c) rearranging the acyl derivative compound of the fifth formula under acidic conditions so as to give an acyl indane compound of a sixth formula; and d) hydrolysing the acyl group of the acyl indane compound of the sixth formula so as to obtain the 4-aminoindane derivatives of the first formula.

The present invention relates to a process for the preparation of4-aminoindane derivatives of Formula (I)

The present invention also relates to a process for the preparation ofaminoindane amides of Formula (II), having fungicidal activity, startingfrom a 4-aminoindane derivative intermediate of Formula (I) obtainedthrough the above-mentioned process.

BACKGROUND OF THE INVENTION

Aminoindane amides as well as the processes for the preparation thereofhave been widely reported in the prior art, such as in JP1070479,JP1117864, JP1313402, JP2157266, JP2249966, JP3077381, JP62096471,EP199822, EP256503, EP276177, EP280275, EP569912, U.S. Pat. No.5,093,347, WO01/53259, WO2004/018438, WO2004/039789, WO2004/072023,WO2004/103975, WO2005/075452, WO2012/084812 and WO2013/186325.

In particular, WO2013/186325 discloses that the compound3-difluoromethyl-N-(7-fluoro-1,1,3-trimethyl-4-indanyl)-1-methyl-4-pyrazolecarboxamidecan be prepared in four steps starting from 4-fluoroaniline and acetone.These two compounds are first condensed together to form a substituteddihydroquinoline, which is then hydrogenated to afford the correspondingtetrahydroquinoline. The tetrahydroquinoline is then reacted with apyrazole carboxylic acid derivative and the resulting compound issubjected to acid rearrangement to provide the corresponding aminoindaneamide derivative. The 4-step preparation is reported below in Scheme 1.

However, said process is not satisfactory since from a chemical point ofview, the secondary amine in the tetrahydroquinoline ring is quitedifficult to acylate; therefore, forcing reaction conditions such asaddition of an excess of a base and the use of a chlorinated organicsolvent are needed so as to obtain the corresponding acyltetrahydroquinoline. Moreover, the overall yields of this process arerelatively low and lead to a significant loss of the pyrazole acidchloride derivative, which is an expensive material.

It is also known that 4-aminoindane derivatives can be used as keyintermediates for synthesizing aminoindane amide derivative. An exampleof such a synthesis can be found in EP199822, which discloses thataminoindane amide derivatives can be obtained through a condensationreaction between a pyrazole carboxylic acid halide and a 4-aminoindanederivative, as reported below in Scheme 2.

However, in EP199822 there is no indication about the synthetic pathwayfor preparing the 4-aminoindane derivative.

Few prior art documents actually describe a process for the preparationof such 4-aminoindane derivatives.

For example, EP654464 discloses that 4-aminoindane derivatives indiastereoisomerically-enriched form can be obtained in four steps, asreported in Scheme 3: i) condensation between a dihydroquinoline and acarboxylic acid derivative bearing both a chiral center (indicatedwith * in the scheme below) and a terminal leaving group LG; ii)catalytic hydrogenation to provide the correspondingtetrahydroquinoline; iii) addition of a strong acid to obtain thecorresponding 4-aminoindane derivative; and iv) hydrolysis of the amidebond.

However, the above-mentioned process for the preparation of the4-aminoindane derivatives is not satisfactory from an industrial pointof view, since it requires to use a different solvent for each step(i.e. tetrahydrofuran, methanol and sulphuric acid+water+acetic acid inExample 1, Route N. 1, page 9). Therefore, additional operations are tobe performed at the end of any single reaction step in order to avoidfor instance, contamination of the subsequent reaction mixture by aremaining chemical or solvent.

Moreover, the acyl dihydroquinoline and the correspondingtetrahydroquinoline are scarcely soluble in apolar solvents, such asaliphatic hydrocarbons. Consequently, in order to completely convert theacyl dihydroquinoline into the corresponding tetrahydroquinoline, higherreaction temperatures or dilution of the reaction mixture are required.

It is therefore desirable to provide an easier process for preparingaminoindane derivatives, in particular aminoindane amides on a largescale, which would reduce costs and production times.

DESCRIPTION OF THE INVENTION

It has now been surprisingly found that, by inverting the hydrogenationand condensation steps of the process disclosed in EP654464, it ispossible to prepare 4-aminoindanes derivatives and the correspondingaminoindane amides in a simpler and more cost-effective way.

A first object of the present invention is therefore a process for thepreparation of 4-aminoindane derivatives of Formula (I), salts andenantiomers thereof

comprising the following steps:

-   -   a) hydrogenating a 1,2-dihydroquinoline of Formula (IV)

to give a corresponding tetrahydroquinoline of Formula (V)

-   -   b) acylating the tetrahydroquinoline of Formula (V) with a        carboxylic acid derivative of Formula RC(O)LG to afford an acyl        derivative compound of Formula (VI)

-   -   c) rearranging the acyl derivative compound of Formula (VI)        under acidic conditions to give an acyl indane compound of        Formula (VII)

-   -   d) hydrolysing the acyl group of the acyl indane compound of        Formula (VII) to provide the desired 4-aminoindane of Formula        (I),        wherein in said formulae:    -   n is an integer selected within the range from 0 to 3;    -   R is a C₁-C₆ alkyl group, a C₆-C₁₀ aryl group, these groups        being optionally substituted with one or more of: C₁-C₆ alkyl        group, halogen atom;    -   LG is a leaving group selected from: (i) a hydroxy group; (ii) a        halogen atom; (iii) a C₁-C₆ alkylsulfonyloxy group; (iv) a        C₆-C₁₀ arylsulfonyloxy group; (v) a R_(a)COO group wherein R_(a)        is a C₁-C₆ alkyl group, the groups (iii)-(v) being optionally        substituted with one or more halogen atoms.

The process object of the present invention comprises at least the foursteps indicated above, which are carried out in the indicated order.

As evidenced by the experimental data included in the presentdescription, the Applicant has surprisingly found that by inverting thesteps of hydrogenation and condensation (acylation) of the processdisclosed in EP654464 it becomes possible to use only one type oforganic solvent (e.g. an aliphatic hydrocarbon, such as heptane) in thewhole production process of the 4-amnoindane derivatives of Formula (I),thus simplifying the process and reducing its costs and productiontimes.

Moreover, the preparation process according to the present invention canbe advantageously carried out by performing the steps (a) to (c) withoutbeing necessary to isolate and/or purify the intermediate products ofthe Formulae (VI) and (VII) at the end of their respective formationsteps.

The present invention thus provides a more cost-effective route for thepreparation of 4-aminoindane derivatives of Formula (I) as well as ofother compounds of industrial and commercial interest which aretypically prepared starting from these 4-aminoindane derivatives, suchas the aminoindane amides of Formula (II) which can be used asfungicides. According to the presently claimed process, in the step (a)a 1,2-dihydroquinoline of Formula (IV) is first subjected to catalytichydrogenation, as reported below in Scheme 4.

The compound of Formula (IV) is either commercially available or can beprepared, for instance, as described in Organic Synthesis, Vol. III,pag. 329. According to a preferred aspect of the present invention, ananiline derivative of Formula (III) is condensed with acetone inpresence of an acidic catalyst to afford the correspondingdihydroquinoline of Formula (IV), as reported below in Scheme 5.

The aniline derivative of Formula (III) is reacted with acetone, in aquantity comprised between 1 and 15 molar equivalents, preferablybetween 3 and 10 molar equivalents, more preferably between 4 and 7molar equivalents, with respect to the starting aniline of Formula(III).

Preferably, the acetone is added to said aniline derivative of Formula(III) during a time comprised between 1 and 15 hours, more preferablybetween 2 and 12 hours, even more preferably between 5 and 10 hours. Tothe mixture thus formed, an acidic catalyst is added, preferably anacidic catalyst selected from an organic acid, an inorganic acid or amixture thereof. Non-limiting examples of suitable acidic catalystsaccording to the present invention are: methanesulfonic acid,paratoluenesulfonic acid, acetic acid, tetrafluoboric acid, hydrochloricacid, hydrobromic acid, sulfuric acid or mixtures thereof.

Most preferred acidic catalysts are selected from tetrafluoboric acidand paratoluenesulfonic acid.

During the addition of the acetone to the aniline derivative of Formula(III), the reaction mixture is kept at a temperature comprised between80° C. and 200° C., preferably between 100° C. and 180° C., morepreferably between 125° C. and 145° C.

When the reaction is complete, the dihydroquinoline derivative ofFormula (IV) thus obtained can be isolated and purified according tomethods well known to those skilled in the art. For example, thereaction mixture can be treated with a base, such as an inorganic base,to remove free acidity and extracted by mixing it with an organicsolvent slightly-miscible or immiscible with water. The desired1,2-dihydroquinoline product can be recovered for instance by fractionaldistillation.

According to a preferred aspect of the present invention, the residualaniline derivative of Formula (III) can also be recovered by fractionaldistillation and advantageously reused in the subsequent productionbatch.

According to the present invention, in the step (a) the compound ofFormula (IV) is dissolved in an organic solvent, preferably a polarorganic solvent, and a metal catalyst is added to the reaction mixture.

Said metal catalyst is preferably an heterogeneous catalyst, morepreferably selected from palladium on charcoal, palladium hydroxide oncharcoal, Raney nickel and platinum oxide; even more preferably themetal catalyst is palladium on charcoal.

According to the present invention, the catalyst loading is comprisedbetween 0.05 and 0.7%, preferably comprised between 0.1 and 0.6%, morepreferably the loading is of about 0.5%, with respect to the molaramount of dihydroquinoline of Formula (IV). Non-limiting examples ofsolvents that can be used in the hydrogenation reaction are: aliphaticor cycloaliphatic hydrocarbons (e.g. petroleum ether, hexane,cyclohexane, heptane), chlorinated hydrocarbons (e.g. methylenechloride, chloroform, carbon tetrachloride, dichloroethane), aromatichydrocarbons (e.g. benzene, toluene, xylene, chlorobenzene), alcoholsand glycols (e.g. methanol, ethanol, isopropanol, ethylene glycol),esters (e.g. ethyl acetate, butyl acetate) or mixtures thereof.

Among these, the preferred solvents are: aliphatic hydrocarbons, such ashexane and heptanes; chlorinated hydrocarbons, such as methylenechloride and dichloroethane; alcohols, such as methanol, ethanol andisopropanol; toluene; ethyl acetate.

Heptane, dichloroethane, methanol and toluene are particularlypreferred.

Within the meaning of the present invention, the term “heptane” referseither to n-heptane or to a mixture of isomers.

As it is well known to the skilled person, the hydrogenation reaction ofstep a) can be carried out at a pressure greater than 1 bar or atatmospheric pressure.

Preferably, the step a) of the present invention is carried out atatmospheric pressure.

When the step a) is carried out at atmospheric pressure, the catalystloading is preferably of about 0.5% and the reaction mixture is left toreact for a time preferably comprised between 1 and 5 hours at roomtemperature.

When the step a) is carried out under a hydrogen overpressure, saidoverpressure is preferably comprised between 5 to 9 bar.

When the step a) is carried out under a hydrogen overpressure, thecatalyst loading is preferably comprised between 0.1 and 0.6% and thereaction mixture is left to react for a time preferably comprisedbetween 10 and 18 hours at a temperature preferably comprised between 35and 50° C.

At the end of step (a), the catalyst is recovered and preferably reusedfor subsequent production batches.

The tetrahydroquinoline of Formula (V) obtained in the hydrogenationstep a) is isolated from the reaction mixture by methods well known tothose skilled in the art, for example by solvent concentration.

Preferably, the isolated compound of Formula (V) is not purified and itis used as such in the subsequent step of the process.

Step b) of acylation is performed by adding a carboxylic acid derivativeof Formula RC(O)LG to the tetrahydroquinoline of Formula (V), asreported below in Scheme 6.

in which:

-   -   R is a C₁-C₆ alkyl group, a C₆-C₁₀ aryl group, these groups        being optionally substituted by one or more of: C₁-C₆ alkyl        groups, halogen atoms;    -   LG is a leaving group selected from: (i) a hydroxyl group; (ii)        a halogen atom; (iii) a C₁-C₆ alkylsulfonyloxy group; (iv) a        C₆-C₁₀ arylsulfonyloxy group; (v) a R_(a)COO group wherein R_(a)        is C₁-C₆ alkyl group, the groups (iii)-(v) being optionally        substituted with one or more halogen atoms.

Preferably, the carboxylic acid derivative is added in an amountcomprised between 5 and 30%, more preferably between 10 and 25%, withrespect to the molar quantity of the starting tetrahydroquinoline ofFormula (V). According to a more preferred aspect, the carboxylic acidderivative is selected from acetyl chloride and acetic anhydride, evenmore preferably the carboxylic acid derivative is acetic anhydride.

The acylation reaction can be carried out in an organic solvent or inthe absence of a solvent. According to the present invention, saidreaction is preferably carried out in the absence of any added solvent.

In the step c), the reaction mixture is maintained at a temperaturecomprised between 80° C. and 200° C., preferably comprised between 100°C. and 150° C., more preferably of about 130° C.

If the acetic anhydride is used, once the conversion is complete, somewater is preferably added to cause decomposition of the residual aceticanhydride to acetic acid.

In order to completely remove the residual acetic acid, a solventimmiscible with water can be added to the reaction mixture, preferablyan aliphatic hydrocarbon such as hexane or heptane.

According to a preferred aspect of the present invention, the aceticacid is removed from the reaction mixture by vacuumdistillation/azeotropic distillation with heptane.

The acyl tetrahydroquinoline of Formula (VI) obtained at the end of theacylation step can be purified according to methods well known to theskilled person, for example, by precipitation, crystallization and thelike.

Preferably, said acyl tetrahydroquinoline of Formula (VI) is subjectedto crystallization with an organic solvent thus forming a slurry withthat solvent. Advantageously, according to the present invention, thesolvent used for the crystallization is of the same type as the solventused for removing the residual acetic acid.

The acyl tetrahydroquinoline of Formula (VI) contained in said slurry ispreferably not isolated. The slurry can be used as such in the nextstep.

Subsequently, the acyl tetrahydroquinoline of Formula (VI) is subjectedto rearrangement in acidic environment, as reported below in Scheme 7.

The acidic pH condition which allows the rearrangement of thetetrahydroquinoline of Formula (VI) to give the corresponding indanederivative of Formula (VII) can be obtained by addition of an organic orinorganic acid to the compound of Formula (VI).

Preferably, an inorganic acid is added, more preferably an inorganicacid selected from orthophosphoric acid and sulfuric acid, even morepreferably the inorganic acid is sulfuric acid.

Said inorganic or organic acid is added in an amount comprised between 3and 10 molar equivalents, preferably between 4 and 9 molar equivalents,more preferably between 6 and 7 molar equivalents, with respect to thetetrahydroquinoline of Formula (VI). According to a more preferredaspect of the present invention, the concentration of the acid iscomprised between 80% and 98%, even more preferably between 90% and 97%.

Since the acid dissolution is exothermic, the temperature of thereaction mixture is to be controlled.

Therefore, according to the presently claimed process, the reactionmixture is preferably kept at a temperature comprised between 10° C. and60° C., more preferably between room temperature (25° C.) and 40° C.Preferably, the reaction mixture is left to react for a time comprisedbetween 10 and 30 hours, more preferably between 15 and 25 hours, evenmore preferably of about 20 hours, in order to obtain a substantiallycomplete conversion of the tetrahydroquinoline into the correspondingindane derivative of Formula (VII). Advantageously, once therearrangement reaction of step c) is complete, the acyl indane ofFormula (VII) is not isolated and the reaction mixture is used as suchin the next hydrolysis step d), as reported below in Scheme 8.

In step d), the reaction mixture of step c) containing the acyl indaneof Formula (VII) is diluted with water so as to preferably obtain anacid concentration in the reaction mixture comprised between 30% and 70%by weight, more preferably between 40% and 60%, even more preferably ofabout 50%.

The reaction mixture is then brought to a temperature preferablycomprised between 60° C. and the reflux temperature, more preferablybetween 95° C. and 110° C. After a few hours at the selectedtemperature, the corresponding 4-aminoindane is formed, as acid additionsalt of Formula (VIII).

Said salt of Formula (VIII) can be isolated and purified according tomethods well known to those skilled in the art, such as precipitation orcrystallization.

According to a preferred aspect of the present invention, the salt canbe precipitated by adding water and the organic impurities can beremoved by adding an organic solvent, preferably a solvent immisciblewith water, such as an aliphatic hydrocarbon, more preferably heptane.

Subsequently, the acid addition salt of 4-aminoindane (VIII) issuspended in water and a basic solution is added so as to obtain thedesired 4-aminoindane of Formula (I) in free form. The basic solution ispreferably added in an amount comprised between 10% and 80% molarexcess, more preferably comprised between 40% and 60% molar excess withrespect to the amount of the salt of formula (VIII).

Non-limiting examples of bases suitable for the present invention arealkaline metal hydroxides, such as sodium hydroxide and potassiumhydroxide, or alkaline metal carbonates.

Particularly preferred bases according to the present invention arealkaline metal hydroxides.

After the addition of the basic solution, the reaction mixture is leftto react at a temperature comprised between 35° C. and 70° C.,preferably between 40° C. and 60° C., more preferably of about 55° C.

As it is well known to the skilled person, different techniques can beused in order to isolate the desired product of Formula (I); forinstance, the reaction mixture can be extracted by mixing it with anorganic solvent slightly-miscible or immiscible with water, preferablyheptane, and the organic layer can be filtered so as to remove the solidresidues.

According to the present invention, the organic solution containing the4-aminoindane of Formula (I) obtained at the end of the step (d) ispreferably not concentrated and, advantageously, can be used as such forthe preparation of the aminoindane amides of Formula (II).

A further object of the present invention is a process for thepreparation of aminoindane amides of Formula (II),

comprising the steps of:

-   -   preparing at least one 4-aminoindane derivative of Formula (I)        by carrying out the steps (a)-(d) of the process described        above;    -   condensing said 4-aminoindane derivative of Formula (I) with at        least one compound of Formula

AC(O)X

wherein in said formulae:

-   -   A represents a C₆-C₁₀ aryl group or a heterocyclic ring with 5        or 6 atoms containing from 1 to 3 heteroatoms selected from N,        O, S, these groups being optionally substituted by one or more        R₁ and R₂ groups;    -   R₁ represents a C₁-C₆ alkyl group or a C₁-C₆ haloalkyl group,        said groups being optionally substituted with one or more groups        selected from R′, OR′, S(O)_(m)R′; or R₁ represents a C₃-C₆        cycloalkyl group, a C₄-C₉ cycloalkylalkyl group, a C₂-C₆ alkenyl        group, a C₂-C₆ alkinyl group, a C₆-C₁₀ aryl group, a C₇-C₁₂        arylalkyl group, a heterocyclic ring with 5 or 6 atoms        containing from 1 to 3 heteroatoms selected from N, O, S, these        groups being optionally substituted by one or more groups        selected from halogen atoms, R′, OR′, NR′R″, S(O)_(m)R′,        CONR′R″, COR′, CO₂R′, CN, NO₂;    -   R₂ represents a C₁-C₆ alkyl group or a C₁-C₆ haloalkyl group,        said groups being optionally substituted with one or more groups        selected from R′, OR′, S(O)_(m)R′; or R₂ represents a C₃-C₆        cycloalkyl group, a C₄-C₉ cycloalkylalkyl group, a C₆-C₁₀ aryl        group, a C₇-C₁₂ arylalkyl group, these groups being optionally        substituted by one or more groups selected from halogen atoms,        R′, OR′, S(O)_(m)R′, NR′R″, CONR′R″, COR′, CO₂R′, NO₂, CN;    -   R′ and R″ represent a hydrogen atom, a C₁-C₄ alkyl group, a        C₁-C₄ haloalkyl group;    -   X represents a hydroxyl group, halogen, a C₁-C₆ alkoxy group, a        C₁-C₆ alkylsulfonyloxy group, a C₆-C₁₀ arylsulfonyloxy group,        these groups being optionally substituted by one or more halogen        atoms;    -   n is an integer selected within the range from 0 to 3;    -   m is an integer selected within the range from 0 to 2.

Examples of a C₁-C₆ alkyl group are methyl, ethyl, propyl, butyl,pentyl, hexyl.

Examples of a C₁-C₆ haloalkyl group are dichloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, chloro-difluoromethyl, dichloroethyl,trifluoroethyl, tetra-fluoroethyl, pentafluoroethyl, tetrafluoropropyl,pentafluoropropyl, dichlorobutyl, difluorobutyl, dichloropentyl,difluoropentyl, dichlorohexyl, difluorohexyl.

Examples of a C₃-C₆ cycloalkyl group are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl.

Examples of a C₄-C₉ cycloalkylalkyl group are cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl,cyclohexylpropyl.

Examples of a C₂-C₆ alkenyl group are ethenyl, propenyl, butenyl,pentenyl, hexenyl.

Examples of a C₂-C₆ alkinyl group are ethinyl, propinyl, butinyl,pentinyl, hexinyl.

Examples of a C₆-C₁₀ aryl group are phenyl, naphthyl.

Examples of a C₇-C₁₂ arylalkyl group are benzyl, phenylethyl,phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, naphthylmethyl,naphthylethyl.

Examples of a heterocyclic ring with 5 or 6 atoms containing from 1 to 3heteroatoms selected from N, O, S, are pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiadiazolyl, oxadiazolyl, furanyl, thiophenyl, pyridyl,pyrimidyl, triazinyl.

Examples of a heterocyclic nitrogenated ring with 5 or 6 atoms arepyrrolidyl, piperidyl, morpholyl.

Examples of halogen atoms are fluorine, chlorine, bromine, iodine.

Among the aminoindane amides having general formula (II) that can beprepared with the process of the present invention, preferred are thosewherein:

-   -   A represents one of the following heterocycles A₁-A₅:

-   -   R₁ represents a C₁-C₆ alkyl group, a C₁-C₆ haloalkyl group or a        phenyl group optionally substituted with halogen atoms, C₁-C₄        alkyl groups, C₁-C₄ haloalkyl groups, C₁-C₄ alkoxyl groups,        C₁-C₄ haloalkoxyl groups;    -   R₂ represents a C₁-C₆ alkyl group, a C₁-C₆ haloalkyl group, or a        phenyl group optionally substituted with halogen atoms, C₁-C₄        alkyl groups, C₁-C₄ haloalkyl groups, C₁-C₄ alkoxyl groups,        C₁-C₄ haloalkoxyl groups;

Particularly preferred are the products having formula (II) wherein:

-   -   R₁ represents a C₁-C₆ alkyl group or a phenyl optionally        substituted by halogen atoms;    -   R₂ represents a methyl, a difluoromethyl, a trifluoromethyl or a        phenyl optionally substituted by halogen atoms;

Even more preferred are the products having general formula (II)wherein:

-   -   A represents A₁;    -   R₁ represents a methyl;    -   R₂ represents a methyl, a difluoromethyl, a trifluoromethyl.

According to a preferred aspect of the present invention, a carboxylicacid derivative of Formula AC(O)X is added to the solution of4-aminoindane of Formula (I) obtained in step d), preferably in a molarratio comprised between 0.9 and 1.1, more preferably between 0.95 and1.05, even more preferably in equimolar amount with respect to thequantity of 4-aminoindane of Formula (I).

Preferably, said carboxylic acid derivative of Formula AC(O)X is an acidchloride, i.e. X represents a chlorine atom.

After the addition of the acid derivative, the reaction mixture isbrought to a temperature comprised between 60° C. and the refluxtemperature of the hydrocarbon solvent, preferably between 95° C. and100° C. At the end of the condensation step, the reaction mixture can becooled and an alkaline aqueous solution added in order to neutralizeresidual acidity.

The aminoindane amide of Formula (II) formed at the end of thecondensation step can be subsequently isolated and possibly purifiedaccording to well-known techniques, for instance, by precipitation andsubsequent filtration and washing of the solid product. The fact thatthe final aminoindane amide product can be isolated by filtration fromthe reaction mass represents a further advantage of the presentinvention with respect to the preparation process of the prior art.

The following examples are provided for illustrative purposes of thepresent invention and should be considered as being descriptive andnon-limiting of the same.

EXPERIMENTAL PART Example 1 a) Preparation of6-fluoro-2,2,4-trimethyl-1,2-dihydroquinoline (IV)

Reaction

In a one-litre round-bottomed flask under nitrogen blanketing4-fluoroaniline (III) (445 grams, 4.0 mol) is charged, together withHBF₄ (48% aqueous solution, 56 grams, 0.32 mol) and 50 mL acetone.

The flask is fitted with thermometer and a glass distillation system,comprising a vertical column filled with coarse glass rings, andcondenser. An efficient magnetic stirring is employed.

The flask is heated in an external bath, set at the temperature of150-155° C.

When the internal temperature reaches 120° C. and condensate startsbeing collected at the distillation end, the addition of acetone isstarted. Acetone is fed through PTFE tubing, ending near the bottom ofthe reaction mass, at the constant rate of approximately. 150-175mL/hour, so as to maintain a very slow distillation rate. The internaltemperature of the reaction is maintained in the interval 132-140° C. Anoverall time of 8-10 hours is employed for the supply of acetone (1500mL), after which the reaction is stirred for further 20 min at 140° C.;the reaction mass is then cooled below 40° C.

Distillation

The distillation is performed in the same reaction vessel, maintainingthe same fractioning column. The reaction mass is subjected topreliminary evaporation at 50° C. at 20-40 mbar to complete acetone andwater removal.

Vacuum is applied in the range 2.0-3.0 mbar. The flask is heated, withtemperature of the external bath progressively increased and reachingthe final maximum of 170° C., at which the collection of the product iscompleted, with vacuum increased to 1.0 mbar.

Four main fractions are separated.

-   -   1. Distillate at 49-52° C. (head temperature), constituted        mainly of Fluoroaniline (ca. 98%).    -   2. Distillate at 52-90° C., small amount of mixed fractions (4        grams).    -   3. Distillate at 92-102° C. constituting the product        dihydroquinoline.    -   4. Residue in the flask: dark dense material (tars), that        solidifies on cooling.

The results of the representative experiment, including the recovery ofFluoroaniline, in term of weight and molar yields were:

-   -   Dihydroquinoline (as ca. 95% GCA purity distilled material): 340        grams, ca. 42%    -   Dihydroquinoline yield (overall available): ca. 43%    -   Recovered 4-Fluoroaniline yield (overall available): ca. 42%    -   Dihydroquinoline yield, calculated on consumed 4-Fluoroaniline:        ca. 72%

Distilled 4-Fluoroaniline and any mixed fractions are sent to recycle ina successive batch.

b) Preparation of 6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline(V)

The crude liquid Dihydroquinoline (IV) (96% purity, 106 grams, 0.530mol) is dissolved in 400 mL heptane and extracted with 200 mL 1% aqueoushydrochloric acid. The aqueous layer is discarded and the organicsolution is transferred to a 1-litre hydrogenation autoclave. Catalyticpalladium on carbon (10%, 2.5 grams) is charged, hydrogen gas isintroduced at 3 bar pressure and reaction performed at 30° C. for 2hours.

After filtration of the catalyst, the solvent is completely removed bydistillation, thus obtaining 100.0 grams crude Tetrahydroquinoline (V),having purity 98.5%.

c) Preparation of1-acetyl-6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (VI)

In a one-litre round-bottomed flask with mechanical stirring undernitrogen blanketing, Tetrahydroquinoline (V) (98% purity, 100.0 grams,0.506 mol) is mixed with acetic anhydride (60.0 grams, 0.58 mol).

The reaction mixture is heated in an external bath, set at thetemperature of 150° C., with internal temperature reaching 134 to 138°C. at which it is maintained for 5 hours. Further excess aceticanhydride (1.0 g) can be added to achieve complete conversion.

The reaction mixture is refrigerated to ca. 40° C., and water (2.0 mL)is added to decompose excess acetic anhydride.

The liquid (acetic acid) is distilled from the reaction vessel atreduced pressure (60 mbar and then 20 mbar; with temperature in therange 70-90° C.).

The semi-solid residue is consequently taken up with heptane (300 mL)and again subjected to complete distillation at atmospheric pressure,with internal temperature 98-124° C., in order to completely removeacetic acid.

More heptane (150 mL) is added, so as to obtain a complete solution at95° C. The mass is then allowed to cool slowly to 20° C. with stirring,in order to cause the precipitation of a finely divided solid product.

d) Preparation of 7-fluoro-1,1,3-trimethylindan-4-ylamine sulfate (VIII)

In a one-litre round-bottomed flask with mechanical stirring sulfuricacid (93% concentration, 375 grams, 3.50 mol) is initially charged.

The acetyl-tetrahydroquinoline (VI) (119 grams, 0.50 mol) heptanesuspension from step c is slowly added into the sulfuric acid layer withefficient stirring while the mass temperature is controlled between 15and 20° C. The resulting biphasic suspension is then maintained withstirring at 34-36° C. for 20 hours.

One additional hour with temperature increased to 48-50° C. is allowedfor completing the conversion.

To the reaction mass water (320 mL) is slowly added under stirring withstrong exotherm (in order to obtain ca. 50% H₂SO₄ concentration). Thereaction mass is progressively heated and heptane is distilled off, withcollection of organic layer (170 mL) and some water.

The solution is then heated to a reflux (110-111° C., internaltemperature) and maintained 5 hours.

The reaction mass is refrigerated to 40° C. and slowly poured intoice-cold water (1000 grams) with evident exotherm (in order to obtainca. 20% H₂SO₄ concentration) in a 2-litre vessel with mechanicalstirring. The final temperature is adjusted around 20° C. and theresulting slurry of indanamine sulfate salt (VIII) is filtered. Thesolid is washed on the filter with 150 mL water, followed by heptane(250 mL).

The filtration cake is sucked on the filter for sufficient time, thenthe wet solid (approximately 180 grams) is sent to salt un-blocking.

e) Preparation of 7-fluoro-1,1,3-trimethylindan-4-ylamine (I)

The solid indanamine sulfate salt (total amount, 0.450 mol) is added to400 grams aqueous solution containing NaOH (28 grams, 0.68 mol) in a2-litre flask. To the alkaline suspension heptane (400 mL) is added andthe whole is stirred with heating to 55° C. After complete solidsdissolution, the phases are separated. The aqueous layer is extractedagain with heptane (300 mL) at 55° C. The combined warm heptane solution(540 grams) is filtered on a layer of celite to remove some undissolvedmaterial.

Part of the heptane is distilled off at reduced pressure (275 mbar, 57°C.), in order to azeotropically remove some traces of water and reachthe suitable volume for use in next Step. The final weight of thesolution is approximately 460 grams, containing around 89.0 gramsindanamine (I)

Example 2 a) Preparation of1-methyl-3-(difluoromethyl)-1H-pyrazole-4-carbonyl chloride (A=A₁ inwhich R₁=methyl, R₂=difluoromethyl)

The pyrazole acid chloride is prepared from3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid and thionylchloride in heptane shortly before use.

In a 500-mL round-bottomed flask provided with alkaline scrubber,pyrazole acid (74.0 grams, 0.42 mol) is suspended in heptane (170 mL).Dimethylformamide (0.70 grams, 0.009 mol) and thionyl chloride (55.0grams, 0.462 mol) are added and the bi-phasic mixture is stirred andheated at 42-45° C.

After complete conversion of pyrazole acid (2.5 hours), the solvent andexcess thionyl chloride are completely removed by vacuum distillation.

Liquid pyrazole acid chloride is obtained as the residue (approximately81.0 grams).

b) Preparation of3-difluoromethyl-N-(7-fluoro-1,1,3-trimethyl-4-indanyl)-1-methyl-4-pyrazolecarboxamide(II), A=A₁ in which R₁=methyl, R₂=difluoromethyl

A 2-litre glass reactor with efficient mechanical stirrer, refluxcondenser and alkaline scrubber is employed.

To the indanamine heptane solution (I) (total amount, 460 grams, 0.46mol indanamine) at 50° C., the liquid pyrazole acid chloride obtained instep a) is added during ca. 10 min at 50-70° C. with exothermic reactionand formation of a precipitate. More heptane (20 mL) is used forrinsing.

The reaction is stirred at reflux (95-97° C. internal temperature)during 4 hours, after which the reaction is completed. The evolution ofHCl ceases within 3 hours.

The resulting reaction suspension is refrigerated below 30° C., thenNaOH aqueous solution (215 mL, 2.5% concentration) is added, and themixture stirred at least 30 min, while the temperature is adjusted to22° C.

The slurry is filtered on a flat sintered glass filter and the solidwashed at 45° C. with water (250 mL) after re-slurrying and stirring.

The resulting solid is filtered again and washed on the filter withwater, (250 mL, or until resulting pH is neutral) and successively withheptane (250 mL).

After aspiration on the filter for 1 hour, the moist solid (165 grams)is dried in a vacuum oven at 55° C.

The desired product is obtained (approximately 140 grams, with assay98%).

Heptane mother liquors contain excess indanamine, which is sent torecycle.

Example 3 (Comparative) a) Preparation of6-fluoro-2,2,4-trimethyl-1,2-dihydroquinoline

Step 1 is run according to Example 1, step a). In addition, theresulting distilled dihydroquinoline is dissolved in a proper solventand stirred with 1% aqueous solution of hydrochloric acid, in order toremove any residual 4-fluoroaniline and reach around 98% purity. Saidsolvent is removed by vacuum distillation before running the followingstep.

b) Preparation of 1-acetyl-6-fluoro-2,2,4-trimethyl-1,2-dihydroquinoline

In a one-litre round-bottomed flask with mechanical stirring undernitrogen blanketing, Dihydroquinoline (98% purity, 104.0 grams, 0.533mol) is mixed with acetic anhydride (65.0 grams, 0.635 mol).

The reaction mixture is heated in an external bath, set at thetemperature of 150° C., with internal temperature reaching around 138°C. at which it is maintained for 5 hours to achieve complete conversion.

The reaction mixture is refrigerated to ca. 40° C., and water (3.0 mL)is added to decompose excess acetic anhydride.

The liquid (acetic acid) is distilled from the reaction vessel atreduced pressure (60 mbar and then 20 mbar; with temperature in therange 70-90° C.).

The oily residue is consequently taken up with heptane (300 mL) andagain subjected to complete distillation at atmospheric pressure, withinternal temperature 96-125° C., in order to completely remove aceticacid.

More heptane (500 mL) is added, so as to obtain a complete solution at65° C. The mass is kept at temperature around 50° C. and transferred tothe following stage.

c) Preparation of1-acetyl-6-fluoro-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline

The organic solution is transferred to a 1-litre hydrogenation autoclaveunder nitrogen. Catalytic palladium on carbon (10%, 2.5 grams) ischarged, hydrogen gas is introduced at 3 bar pressure and reactionperformed at 50° C. for 2 hours.

After filtration of the catalyst, the solvent is partly removed byvacuum distillation, and eventually refrigerated to 20° C., thusobtaining 119 grams crude acetyl-THQ, having purity 98%, as theapproximately 240 grams heptane suspension.

d) Preparation of 7-fluoro-1,1,3-trimethylindan-4-ylamine

In a one-litre round-bottomed flask with mechanical stirring sulfuricacid (93% concentration, 375 grams, 3.50 mol) is initially charged.

The acetyl-THQ (119 grams, 0.50 mol) heptane suspension from Step 3 isslowly added into the sulfuric acid layer with efficient stirring whilethe mass temperature is controlled between 15 and 20° C. The resultingbiphasic suspension is then maintained with stirring at 34-36° C. during20 hours.

One additional hour with temperature increased to 48-50° C. is allowedfor completing the conversion.

To the reaction mass water (320 mL) is slowly added under stirring withstrong exotherm (in order to obtain ca. 50% H₂SO₄ concentration). Thereaction mass is progressively heated and heptane is distilled off, withcollection of organic layer (170 mL) and some water.

The solution is then heated to a reflux (110-111° C., internaltemperature) and maintained 5 hours.

The reaction mass is refrigerated to 40° C. and slowly poured intoice-cold water (1000 grams) with evident exotherm in a 2-litre vesselwith mechanical stirring. The final temperature is adjusted around 20°C. and the resulting slurry of indanamine sulfate salt is filtered. Thesolid is washed on the filter with 150 mL water, followed by heptane(250 mL).

The wet filtration cake is then added to 400 grams aqueous solutioncontaining NaOH (28 grams, 0.68 mol) in a 2-litre flask. To the alkalinesuspension heptane (400 mL) is added and the whole is stirred withheating to 55° C. After complete solids dissolution, the phases areseparated. The aqueous layer is extracted again with heptane (300 mL) at55° C. The combined warm heptane solution (540 grams) is filtered on alayer of celite to remove some undissolved material.

When heptane is completely distilled off at reduced pressure, a darksolid residue is obtained, constituted of approximately 89.0 gramsindanamine free-base, having purity above 99%.

1. A process for preparation of 4-aminoindane derivatives of Formula(I), salts and enantiomers thereof

comprising the steps of: a) hydrogenating a 1,2-dihydroquinoline ofFormula (IV)

to give a corresponding tetrahydroquinoline of Formula (V)

b) acylating the tetrahydroquinoline of Formula (V) with a carboxylicacid derivative of Formula RC(O)LG to obtain a corresponding acylderivative compound of Formula (VI)

c) rearranging the acyl derivative compound of Formula (VI) under acidicconditions so as to give an acyl indane compound of Formula (VII)

and d) hydrolysing the acyl group of the acyl indane compound of Formula(VII) so as to obtain the 4-aminoindane derivatives of Formula (I);wherein in the formulae: n is an integer selected within the range from0 to 3, inclusive; R is selected from a C₁-C₆ alkyl group or a C₆-C₁₀aryl group, these groups being optionally substituted with one or moreof: C₁-C₆ alkyl groups, halogen atoms; and LG is a leaving groupselected from: (i) a hydroxy group; (ii) a halogen atom; (iii) a C₁-C₆alkylsulfonyloxy group; (iv) a C₆-C₁₀ arylsulfonyloxy group; (v) aR_(a)COO group wherein R_(a) is a C₁-C₆ alkyl group, the groups(iii)-(v) being optionally substituted with one or more halogen atoms.2. The process of claim 1, wherein the step (a) comprises contacting the1,2-dihydroquinoline of Formula (IV) dissolved in an organic solventwith gaseous hydrogen in a presence of a hydrogenation catalyst so as toobtain the tetrahydroquinoline of Formula (V).
 3. The process of claim1, wherein the carboxylic acid derivative of Formula RC(O)LG is selectedfrom acetyl chloride, acetic anhydride, or mixtures thereof.
 4. Theprocess of claim 1, wherein the step (b) is carried out in an absence ofadded solvent.
 5. The process of claim 1, wherein a reaction mixtureobtained at an end of the step (b) is added with organic solvent andthen subjected to distillation to remove an excess of the carboxylicacid derivative and to form a slurry containing the acyl derivativecompound of Formula (VI).
 6. The process of claim 5, wherein the slurrycontaining the acyl derivative compound of Formula (VI) is fed to thestep (c).
 7. The process of claim 1, wherein the step (c) comprisessuspending the acyl derivative compound of Formula (VI) in an organicsolvent and contacting the thus obtained suspension with an organic acidor an inorganic acid so as to obtain the acyl indane compound of Formula(VII) in a form of an addition salt.
 8. The process of claim 1, whereinthe step (d) comprises contacting the acyl indane compound of Formula(VII) with water.
 9. The process of claim 7, wherein a slurry containingthe acyl indane compound of Formula (VII) is fed to the step (d). 10.The process of claim 7, wherein the acyl indane compound of Formula(VII) in the form of the addition salt is contacted with an alkalineaqueous solution so as to obtain the 4-aminoindane derivatives ofFormula (I).
 11. The process of claim 2, wherein the organic solvent isselected from: aliphatic or cycloaliphatic hydrocarbons, chlorinatedhydrocarbons, aromatic hydrocarbons, alcohols, glycols, esters, ormixtures thereof.
 12. The process of claim 2, wherein the organicsolvent is selected from: hexane, heptane, methylene chloride,dichloroethane, methanol, ethanol, isopropanol, toluene, ethyl acetate,or mixtures thereof.
 13. A process for preparation of aminoindane amidesof Formula (II),

comprising the steps of: preparing at least one 4-aminoindane derivativeof Formula (I) by carrying out the steps (a)-(d) of the process of claim1; and condensing the 4-aminoindane derivative of Formula (I) with atleast one compound of Formula AC(O)X; wherein in the formulae: Arepresents a C₆-C₁₀ aryl group or a heterocyclic ring with 5 or 6 atomscontaining from 1 to 3 heteroatoms selected from N, O, S, these groupsbeing optionally substituted by one or more R₁ and R₂ groups; R₁represents a C₁-C₆ alkyl group or a C₁-C₆ haloalkyl group, the groupsbeing optionally substituted with one or more groups selected from R′,OR′, S(O)_(m)R′; or R₁ represents a C₃-C₆ cycloalkyl group, a C₄-C₉cycloalkylalkyl group, a C₂-C₆ alkenyl group, a C₂-C₆ alkinyl group, aC₆-C₁₀ aryl group, a C₇-C₁₂ arylalkyl group, a heterocyclic ring with 5or 6 atoms containing from 1 to 3 heteroatoms selected from N, O, S,these groups being optionally substituted by one or more groups selectedfrom halogen atoms, R′, OR′, NR′R″, S(O)_(m)R′, CONR′R″, COR′, CO₂R′,CN, NO₂; R² represents a C₁-C₆ alkyl group or a C₁-C₆ haloalkyl group,the groups being optionally substituted with one or more groups selectedfrom R′, OR′, S(O)_(m)R′; or R₂ represents a C₃-C₆ cycloalkyl group, aC₄-C₉ cycloalkylalkyl group, a C₆-C₁₀ aryl group, a C₇-C₁₂ arylalkylgroup, these groups being optionally substituted by one or more groupsselected from halogen atoms, R′, OR′, S(O)_(m)R′, NR′R″, CONR′R″, COR′,CO₂R′, NO₂, CN; R′ and R″ represent a hydrogen atom, a C₁-C₄ alkylgroup, a C₁-C₄ haloalkyl group; X represents a hydroxyl group, ahalogen, a C₁-C₆ alkoxy group, a C₁-C₆ alkylsulfonyloxy group, a C₆-C₁₀arylsulfonyloxy group, these groups being optionally substituted by oneor more halogen atoms; n is an integer selected within the range from 0to 3, inclusive; and m is an integer selected within the range from 0 to2, inclusive.
 14. The process of claim 1, wherein the step (a) comprisescontacting the 1,2-dihydroquinoline of Formula (IV) dissolved in a polarsolvent with gaseous hydrogen in a presence of a hydrogenation catalystso as to obtain the tetrahydroquinoline of Formula (V).
 15. The processof claim 1, wherein the step (c) comprises suspending the acylderivative compound of Formula (VI) in an organic solvent and contactingthe thus obtained suspension with sulphuric acid or orthophosphoric acidso as to obtain the acyl indane compound of Formula (VII) in a form ofan addition salt.
 16. The process of claim 2, wherein the organicsolvent is selected from: heptane, dichloroethane, methanol, toluene, ormixtures thereof.
 17. The process of claim 5, wherein the organicsolvent is selected from: aliphatic or cycloaliphatic hydrocarbons,chlorinated hydrocarbons, aromatic hydrocarbons, alcohols, glycols,esters, or mixtures thereof.
 18. The process of claim 5, wherein theorganic solvent is selected from: hexane, heptane, methylene chloride,dichloroethane, methanol, ethanol, isopropanol, toluene, ethyl acetate,or mixtures thereof.
 19. The process of claim 7, wherein the organicsolvent is selected from: aliphatic or cycloaliphatic hydrocarbons,chlorinated hydrocarbons, aromatic hydrocarbons, alcohols, glycols,esters, or mixtures thereof.
 20. The process of claim 7, wherein theorganic solvent is selected from: hexane, heptane, methylene chloride,dichloroethane, methanol, ethanol, isopropanol, toluene, ethyl acetate,or mixtures thereof.